Parkinson's disease (PD) is an age-related neurodegenerative disorder affecting approximately 5% of people over age 65. PD is characterized pathologically by the selective degeneration of dopaminergic neurons in the substantia nigra and the formation of intraneuronal inclusions known as Lewy bodies. Existing animal models of PD produce alterations in dopaminergic neurons through genetic or toxic manipulations that may not be relevant to the pathophysiology of PD. We therefore propose to study the molecular pathogenesis of PD through the production of mice bearing genetic modifications that have been implicated in familial PD. The central hypothesis underlying our research is that mutations in the alpha-synuclein gene, recently linked to early-onset familial PD, alter the normal physiology of dopaminergic neurons in the substantia nigra, ultimately leading to their degeneration and production of the parkinsonian phenotype. First, we hypothesize that mutations in alpha-synuclein linked to familial PD (FPD) alter its normal function, resulting in the formation of Lewy bodies and degeneration of dopaminergic neurons. To understand the pathogenicity of mutations in alpha-synuclein, we propose to generate animal models of FPD using transgenic and khockin mice expressing mutant forms of human alpha-synuclein. Second. The alpha-synuclein mutant mice will then be analyzed for biochemical and neuropathological abnormalities associated with PD, such as degeneration of doparninergic neurons and reductions in striatal dopamine levels.